Antibody therapy has gained widespread acceptance as a promising therapeutic strategy to address several diseases including autoimmune disease and cancer. Despite rapid and exciting progress in developing antibody monotherapies and combination treatments, the disease burden attributable to such illnesses has not significantly abated. The complex nature of the normal and pathologic immunologic processes associated with such diseases, coupled with resistance or acquired resistance to antibody treatment, continue to be some of the obstacles to successful advances in patient outcomes.
For example, antibodies specific for the EGFR are now in clinical use for a number of malignancies. Despite their pro-inflammatory side effects, promising results have been shown in some patients treated with anti-EGFR antibodies, either monotherapy or in combination with radio- or chemo-therapy (1). However, a significant proportion of treated patients fail to respond for reasons which have not yet been fully elucidated. An exciting new study in Nature Medicine (2) has shown that some patients carry a mutation in the EGFR which prevents cetuximab binding but not panumitumab binding and thus a further percentage of patients can be screened and be treated with the appropriate anti-EGFR antibody. However, this does not bypass most observed patient resistance. Numerous studies have been carried out to ascertain the mechanism of the noted resistance. EGFR expression is increased in squamous cell carcinoma and other epithelial tumors by several different mechanisms including amplification, gain of expression of the gene and increased rate of EGFR activating mutations.
While specific alterations in EGFR number or function were predicted to affect treatment response, no correlation has been observed in clinical trials (3-7). In 10% of patients resistant to EGFR targeted therapy there are specific activating mutations in the downstream signaling components of the EGFR such as KRAS in the tumors. There is a significant association between absence of response to cetuximab and KRAS status (8-10). A BRAF point mutation, V600E, is one of the most common oncogenic mutations in cells, and a retrospective analysis (11) of patients with metastatic colorectal cancer showed that no BRAF-mutated tumors responded to cetuximab or panitumumab. Analysis of KRAS and BRAF mutational status is now becoming commonplace prior to the use of anti-EGFR antibodies, allowing patients who are unlikely to respond to be selected out and offered alternate treatment such as anti-VEGF therapy. However, these mutations only involve 10% of resistant patients. Mass spectrometry profiling of patient tumor proteomes from responsive versus resistant patients (3) has also been used to predict patient response to EGFR inhibitor treatment but at present the algorithms are not robust enough for use in patient analysis. Attempts to correlate tumor resistance with specific mutations in genes of the EGFR family now involve simultaneous profiling many of genes, which is time-consuming and expensive.